This project explores the fate of CD8+ effector T cells in patients with cancer. Our data show that tumor-infiltrating[unreadable] as well as circulating lymphocytes are susceptible to spontaneous apoptosis in these patients.[unreadable] CD8+ T cells which are particularly susceptible, bind Annexin V and/or have a low level of the T-cell[unreadable] receptor-associated zeta chain. Decreased T-cell numbers and dysfunction of T cells are common findings in[unreadable] patients with head and neck cancer (HNC) and melanoma. We will test the hypothesis that in patients with[unreadable] these cancers, tumor-specific CD8+ T cells are preferentially targeted for apoptosis, which disrupts normal[unreadable] lymphocyte homeostasis and leads to dysregulated anti-tumor responses. In Aim 1, a clinical trial will be[unreadable] performed to in vivo measure absolute production rates of CD4+ and CD8+ cells, their half-life and survival[unreadable] time in the circulation of patients with HNC, using deuterated drinking water to label DMA in these[unreadable] lymphocytes. In addition, TREC and telomere length assays will be performed in a larger cohort of HNC[unreadable] patients to corroborate a rapid T-cell turnover. In Aim 2, we will explore the preferential demise of CD8+[unreadable] effector T cells by a combined use of T-cell surface and apoptosis biomarkers in multi-color flow cytometry.[unreadable] Various T-cell subsets, including tetramer+ tumor-specific T cells in the peripheral circulation of patients with[unreadable] HNC or melanoma will be targeted. Aim 3 will evaluate mechanisms responsible for CD8+ T-cell demise by[unreadable] focusing on the selected molecular targets in the Fas/FasL or mitochondria! pathways of apoptosis.[unreadable] Elimination of CD8+ T cells via a novel mechanism involving circulating membraneous vesicles (MV) will be[unreadable] studied. In Aim 4, effects of the cytokines known to regulate T-cell homeostasis (IL-2, IL-7, IL-12 and IL-15)[unreadable] on the molecular targets engaged in apoptosis will be evaluated as will mechanisms responsible for the[unreadable] protective effects on T cells of the anti-apoptotic protein Mcl-1. In all Aims, efforts will be made to relate[unreadable] expression and function of immune biomarkers studied in CD8+ T cells with the presence and activity of the[unreadable] disease and with the known prognostic factors for the disease. These studies will serve as a basis for the[unreadable] development of novel therapies designed to deliver survival factors to patients with cancer in order to rescue[unreadable] tumor-specific T cells from apoptosis, normalize homeostasis and amplify anti-tumor immune responses.[unreadable]